Administration of fluocinolone acetonide, tretinoin and hydroquinone cream in melasma maintenance therapy

ABSTRACT

Topical application of a triple combination immixture of fluocinolone acetonide, tretinoin and hydroquinone is useful for the maintenance therapy of melasma to prevent hyperpigmentation recurrence or reduce the severity of the hyperpigmentation recurrence.

CROSS-REFERENCE TO PROVISIONAL/PCT APPLICATIONS

This application claims priority under 35 U.S.C. § 119 of U.S.Provisional Application No. 60/875,529, filed Dec. 19, 2006, and is acontinuation/national phase of PCT/EP 2007/064269, filed Dec. 19, 2007and designating the United States (published in the English language onJune 26, 2008 as WO 2008/074848 A1), each hereby expressly incorporatedby reference in its entirety and each assigned to the assignee hereof.

CROSS-REFERENCE TO RELATED APPLICATION

Copending U.S. Patent Application No. ______ [Attorney Docket No.1034227-001016], filed concurrently herewith, each hereby also expresslyincorporated by reference and each also assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

Melasma is an acquired, symmetric, irregular hypermelanosis onsun-exposed areas of the face, commonly seen in Latin American women,particularly those with IV-V skin types (Javaheri S M, Handa S, Kaur Iet al. Safety and efficacy of glycolic acid facial peel in Indian Womenwith melasma. Int. J. Dermatol., 2001;40:354-357).

It is a very frequent disease, although its true incidence is unknown.Many factors have been implicated in the pathogenesis of melasma;however, the most important ones remain UV radiations, hereditarypredisposition, and hormonal dysfunction (Mosher D B, Fitzpatrick T B,Ortonne J-P, Hori Y. Hypomelanoses and Hypermelanoses. In: Freedberg IM, Eisen A Z, Wolff K, et al, eds. Fitzpatrick's Dermatology in GeneralMedicine., Vol.1. New York, N.Y.: McGraw-Hill; 1999: 945-1017; BarankinB, Silver S G, Carruthera A. The skin in pregnancy. J. Cut. Med. Surg.,2002; 6(3): 236-40).

Melasma has historically been difficult to treat and therapy remains achallenge for this chronic condition.

The principal rules of therapy must encompass: sun protection,inhibition of tyrosinase activity, removal of melanin, and destructionor disruption of melanin granules. Pandya and Guevara particularlyrecommend that patients should use sunscreens to protect the skin fromUV-A and UV-B radiation and also from visible light to avoid formationof new melanin and immediate darkening of preformed melanin. Those whoroutinely use a sunscreen along with other treatment modalities dobetter than those who do not (Pandya A G et al. Dermatol. Clin.,2000;18(1):91-98; Vasquez M. Sanchez .J L, The efficacy of a broadspectrum in the treatment of melasma Cutis 193;32:92-96).

Topical treatments are the mainstay (Mosher D B et al. In: Freedberg IM, Eisen A Z, Wolff K, et al, eds. Fitzpatrick's Dermatology in GeneralMedicine., Vol. 1. New York, N.Y.: McGraw-Hill; 1999: 945-1017; Pathak MA et al. J. Am. Acad. Dermato., 1986;15:894-9; Giannotti B, Melli M C.Clin. Drug Invest., 1995; 0(suppl2):57-64)) for the management ofmelasma and current approaches include hydroquinone, considered as thegold standard depigmenting agent and other molecules such as azelaicacid, tretinoin, alpha and beta hydroxy acids, and topicalcorticosteroids used as monotherapy or in various combinations(Giannotti B, Melli M C. Clin. Drug Invest., 1995; 0(suppl2):57-64.;Kimbrough-Green C K, Griffiths CEM, Finkel L J et al. Arch. Dermatol.,1994;130:727-33; Gano S E, Garcia R L. Cutis 1979;23:239-41; Kang W H,Hcun S C, Lee S. J. Dermatol., 1998;25:87-596; Katsambas A, Antoniou CH. J. Eur. Acad. Dermatol. Venereol, 1995;4:217-23; Kligman A M, WillisI. Arch Dermatol., 1975;1 11:40-8.)

Recently, a stable fixed combination cream containing fluocinoloneacetonide (FA), plus hydroquinone (HQ), plus tretinoin (RA) wasdeveloped. Several studies have been performed, comparing this fixedcombination to its three corresponding dyads of active ingredient(FA+HQ), (FA +RA), (HQ+RA). These studies demonstrated better efficacyof the triple combination (FA+HQ+RA) over each dyad, after a 8-weektreatment (Taylor S, Torok H, Jones T, et al. Cutis 2003;72:67-72).

However, melasma being a relapsing disease, there is a real need toaddress how to maintain efficacy achieved after acute treatment. Fivehundred and sixty nine subjects previously treated in the abovementioned studies have been included in a 12-month extension trial toevaluate the safety of the trio fixed combination (Torok H, et al. JDrugs Dermatol., 2005 Sep-Oct;4(5):592-7). The results shown that thetriple combination cream applied once daily over a long-term period issafe and tolerable. But skin atrophy is a primary concern with thelong-term use of topical corticosteroids. However in the extension studymentioned only two cases of skin atrophy were reported. Both cases ofskin atrophy were mild in nature and did not lead to discontinuation inthe study. However, skin atrophy remains a frequent objection ofclinicians to the long-term use of topical medications containingcorticosteroids. For this reason, it is necessary to determine amaintenance therapy use of triple combination cream with such a goodefficacy, good tolerance without side effects. This new regimen can alsobe more attractive to patients who no longer apply the product every daythroughout the period of treatment.

It is stated that in addition to efficacy, the triple combination creamfulfills important requirements of a maintenance therapy which areefficacy with hyperpigmentation improvement, safety with a goodtolerability.

SUMMARY OF THE INVENTION

Surprisingly, it has now been demonstrated that an immixture containingfluocinolone acetonide (FA), hydroquinone (HQ), and tretinoin (RA) asmaintenance therapy is effective to prevent hyperpigmentation recurrenceor reduce the severity of the hyperpigmentation recurrence for a time oftreatment less than 12 months. Indeed, one skilled in the art could nothave foreseen that the treatment with an immixture, which ispreferentially a triple combination cream, containing fluocinoloneacetonide (FA), hydroquinone (HQ), and tretinoin (RA) as maintenancetherapy would delay the recurrence of hyperpigmentation and provide acontinued benefit for 8 months maximum.

The present invention thus provides an effective method of treatingmelasma on a long term basis to prevent recurrence of hyperpigmentationor to control hyperpigmentation recurrence in 8 months maximum. Theinvention features a maximum 6-month maintenance therapy regimen with animmixture containing fluocinolone acetonide (FA), hydroquinone (HQ), andtretinoin (RA) after an initial daily treatment with an immixturecontaining fluocinolone acetonide (FA), hydroquinone (HQ), and tretinoin(RA) during maximum 8 weeks.

This invention more particularly features a maximum 6-month maintenancetherapy regimen with a triple combination cream containing fluocinoloneacetonide (FA), hydroquinone (HQ), and tretinoin (RA) after an initialdaily treatment with a triple combination cream containing fluocinoloneacetonide (FA), hydroquinone (HQ), and tretinoin (RA) during maximum 8weeks.

By maintenance therapy is intended: chronic treatment, long termtreatment, preventive treatment.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

Generally, the present invention features a regimen for treating melasmain a patient which comprises first applying on affected facial areasonce daily an immixture containing fluocinolone acetonide (FA),hydroquinone (HQ), and tretinoin (RA), for maximum 8 weeks (initialtreatment phase); and thereafter applying topically of the sameimmixture cream 3 times a week during a first month, thereafter twotimes a week during a second month and thereafter once a week during athird, fourth, fifth and sixth month.

The present invention more particularly features a regimen for treatingmelasma in a patient which comprises first applying on affected facialareas once daily triple combination cream containing fluocinoloneacetonide (FA), hydroquinone (HQ), and tretinoin (RA), for maximum 8weeks (initial treatment phase); and thereafter applying topically ofthe same triple combination cream 3 times a week during a first month,thereafter two times a week during a second month and thereafter once aweek during a third, fourth, fifth and sixth month.

The said immixture, or dermatological preparation, may comprise 0.001%to 0.5% fluocinolone acetonide, 0.5% to 10% hydroquinone, and 0.01% to1% tretinoin by weight.

The said dermatological preparation may preferentially comprisefluocinolone acetonide 0.01%, hydroquinone 4% and 0.05% tretinoin byweight.

The said immixture, or dermatological composition, may be in the form ofan aqueous gel, cream or lotion, and preferentially formulated as acream.

The present invention features a maintenance treatment of melasma by aninitial treatment with an immixture containing fluocinolone acetonide(FA), hydroquinone (HQ), and tretinoin (RA) once daily for maximum 8weeks followed by topical application of the same immixture 3 times aweek during a first month, thereafter two times a week during a secondmonth and thereafter once a week during a third, fourth, fifth and sixthmonth.

The present invention more particularly features a maintenance treatmentof melasma by an initial treatment with a triple combination creamcontaining fluocinolone acetonide (FA), hydroquinone (HQ), and tretinoin(RA) once daily for maximum 8 weeks followed by topical application ofthe same a triple combination cream 3 times a week during a first month,thereafter two times a week during a second month and thereafter once aweek during a third, fourth, fifth and sixth month. The followingdetails a study that clearly demonstrates the clinical benefit ofmaintenance therapy with triple combination cream containingfluocinolone acetonide (FA) 0.01%, hydroquinone (HQ) 4%, and tretinoin(RA) 0.05%.

A total of 300 subjects with moderate to severe melasma have beenenrolled in a randomized, multi-center, investigator-blind, controlledstudy in different centers. The population to be studied includes maleand female subjects of any race, aged 18 years or older, with a globalmelasma severity score of at least 2 on a scale from 0 (none) to 3(severe).

During the Initial Treatment Phase, subjects have been evaluated atBaseline and at Weeks 2, 4, 6, and 8. The immixture or triplecombination containing fluocinolone acetonide, tretinoine andhydroquinone is topically applied once daily at bedtime to the affectedfacial areas over a period of 8 weeks. At Week 8 (or before if melasmaglobal severity score is 0), all subjects with a melasma global severityscore graded at 0 or 1 are eligible for the Maintenance Phase, and arerandomized in one of the two regimen groups. The first group applied thetriple combination 3 times a week during a first month, thereafter twotimes a week during a second month and thereafter once a week during athird, fourth, fifth and sixth month. The subjects applied the immixtureor triple combination at bedtime on the previously affected areas, aslong as global severity score is below 2 (moderate) for a maximum of 24weeks (6 months).

A sunscreen SPF 60 is applied, during both acute and Maintenance Phase,at least twice daily (morning and mid-day). In case sun exposure cannotbe avoided, re-application is done every two hours.

The subjects are evaluated every 4 weeks during the Maintenance Phase.

Subjects previously enrolled in Initial Treatment Phase treatment andhaving a global severity score of:

-   -   0 (none) if Maintenance Phase starts before the end of the        8-week treatment    -   0 (none) or 1 (mild) if Maintenance Phase starts after the        8-week treatment.

Clinical evaluation of efficacy and safety has been done:

The primary efficacy criterion is the time to relapse during theMaintenance Phase.

The secondary efficacy criteria is:

-   -   global severity score of melasma (full scale)    -   MASI (Melasma Area and Severity Index) score (recorded from        clinical examination at each visit)    -   Subject's static global assessment of melasma (performed at each        visit)

Global severity score of melasma:

The investigator assesses the severity of the subject's melasma (diseaseseverity) at each visit.

The global severity assessment is outlined in the following table:

None 0 Melasma lesions approximately equivalent to surrounding normalskin or with minimal residual hyperpigmentation Mild 1 Slightly darkerthan the surrounding normal skin Moderate 2 Moderately darker than thesurrounding normal skin Severe 3 Markedly darker than the surroundingnormal skin

The time to relapse is defined as the duration between Baseline ofMaintenance Phase and the visit where the relapse occurs. The MelasmaRelapse is derived from the global severity score. Any subject who wasallowed to enter the Maintenance phase [(with a global severity score of0 (before the end of the 8-week (Initial Treatment Phase) or a globalseverity score of 0 or 1 (at week 8)] and who is getting a globalseverity score of at least 2 during this Maintenance phase is defined asa relapse. This is further transformed in a dichotomized variable (norelapse=0 and relapse=1).

Melasma Area and Severity Index (MASI):

The investigator scores (using the scales below) the darkness,homogeneity and area of melasma for further calculation of Melasma Areaand Severity Index (MASI).

Darkness (D) Homogeneity (H) Grading Scale Grading Scale Area (A) Value0 = Absent 0 = Minimal 0 = no involvement 1 = Slight 1 = Slight 1 = <10%2 = Mild 2 = Mild 2 = 10-29% 3 = Marked 3 = Marked 3 = 30-49% 4 = Severe4 = Maximum 4 = 50-69% 5 = 70-89% 6 = 90-100%

The study statistician calculates a computed MASI score at the end ofthe study.

MASI score is used to evaluate the degree of melasma. The MASI systemwas developed by Kimbrough-Green et al. (Kimbrough-Green C K, GriffithsC E M, Finkel L J et al. Arch Dermatol., 1994;130:727-33) and calculatedby the following equation:

MASI=0.3 (DF+HF) AF+0.3 (DMR+HMR) AMR+0.3 (DML+HML) AML+0.1 (DC+HC) AC

Where D is darkness, H is homogeneity, A is area, F is forehead, MR isright malar, ML is left malar, C is chin, and the values 0.3,0.1=respective percentages of the total facial area.

Subject's Static Global Assessment.

A global assessment of melasma will be performed by the subject at eachvisit and graded using the following scoring tool:

0 Completely clear, No evidence of hyperpigmentation 1 Only minor visualevidence of hyperpigmentation 2 Significant evidence ofhyperpigmentation

The Safety assessment is conducted for all subjects at each visit afterenrollment in the study.

All clinical medical events, whether observed by the Investigator orreported by the subject and whether or not thought to be drug-related,is considered adverse events. An adverse event (AE) can be anyunfavorable and/or unintended sign (including an abnormal laboratoryfinding), symptom, or disease temporally associated with the use of amedicinal (investigational) product, whether or not related to themedicinal (investigational) product.

The result is that triple combination is effective, in this regimen inmaintaining the melasma improvement achieved with a previous treatment(12 months).

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference in its entirety.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A regimen for the maintenance therapy of melasma, which comprisestopically applying onto the affected skin areas of an individual in needof such treatment, once daily for a maximum period of 8 weeks, a triplecombination immixture comprising fluocinolone acetonide, hydroquinoneand tretinoin, and continuing such topical application of said triplecombination immixture thereafter for a maximum period of 6 months, at arate of 3 times a week during a first month, thereafter 2 times a weekduring a second month and then once a week during a third, fourth, fifthand sixth month.
 2. The regimen as defined by claim 1, said triplecombination immixture comprising 0.001% to 0.5% fluocinolone acetonide,0.5% to 10% hydroquinone, and 0.01% to 1% tretinoin by weight.
 3. Theregimen as defined by claim 2, said triple combination immixturecomprising 0.01% fluocinolone acetonide, 4% hydroquinone, and 0.05%tretinoin by weight.
 4. The regimen as defined by claim 1, said triplecombination immixture comprising a cream.